Download Cancer Cell Metabolism - Roswell Park Cancer Institute

Cancer Cell Metabolism
Nadi Wickramasekera. Ph.D.
Dept. of Pharmacology and Therapeutics (L4-107)
[email protected]
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An Emerging Hallmark: Reprogramming Energy Metabolism
Acquired Abilities for Cancer Progression: Cancer
Hallmarks 2000 vs 2011
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646
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Lecture Outline
Discuss and review the biochemical pathways involved in anaerobic and
aerobic production of ATP
How is cancer-cell metabolism different?. Warburg theory of cancer or
"Warburg hypothesis -1924”
Cancer cell metabolism: Warburg and beyond. The possible drivers and
advantages of the altered metabolism of cancer cells
Linking oncogenes and tumor suppressor's to tumor cell metabolism
Inhibiting the high glycolytic activity in cancer cells for therapeutic purposes
Mitochondria in cancer cells
Application and integration of tools to study tumor metabolism
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Metabolism (Overview)
Metabolism:
Collection of controlled intracellular biochemical reactions that
convert nutrients and endogenous molecules to energy and
matter (proteins, nucleic acids, and lipids) that sustain life
A sequence of chemical reactions, where the product of one
reaction serves as a substrate for the next, is called a
metabolic pathway or biochemical pathway
Most metabolic pathways take place in specific regions of the
cell
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Map of Metabolic
Pathways
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Basic Chemical Reactions Underlying Metabolism
Catabolism and Anabolism
Two major classes of metabolic reactions
Catabolic pathways
• Break larger molecules into smaller products
• Exergonic (release energy)
Anabolic pathways
• Synthesize large molecules from the smaller
products of catabolism
• Endergonic (require more energy than they release)
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Metabolism Composed of Catabolic and Anabolic Reactions
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Bioenergetics
Cell Energy
ATP is the main energy currency of cells
Formation of ATP
Degradation of glucose and glycogen
-Glycolysis
Oxidative formation of ATP
- Oxidative phosphorylation
Anaerobic pathways
- Do not involve O2
- Glycolysis
Aerobic pathways
- Require O2
- Oxidative phosphorylation
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Basic Steps Involved
1
Glycolysis
2
Acetyl CoA Forma8on
3
Krebs Cycle
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Electron Transport System
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ATP Generating Metabolic Pathways
Aerobic
Anaerobic
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Glycolysis
Glycolysis (“splitting of sugar”) breaks down glucose into two molecules
of pyruvate
Occurs in the cytoplasm and has two major phases
– Energy investment phase
– Energy payoff phase
Occurs whether or not O2 is present
Glycolysis harvests chemical energy by oxidizing glucose to pyruvic acid
The oxidation of glucose to pyruvic acid produces ATP and NADH
Pyruvic
acid
Glucose
Energy yield: 2 ATP and 2 NADH
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Balance Sheet for Glycolysis
Input
1 Glucose
2 ADP + Pi
2 NAD+
Output
2 Pyruvate
2 ATP
2 NADH
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Fate of Pyruvate
Glucose
CYTOSOL
Pyruvate
Anaerobic Respira=on
Aerobic Respira=on
O2 present
Cellular respiration
No O2 present
Fermentation
MITOCHONDRION
Ethanol
or
lactate
Acetyl CoA
Citric
acid
cycle
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Transi=on Reac=on
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Transi8on Reac8on
Krebs Cycle (Citric Acid Cycle)
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Oxidative Phosphorylation
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ATP Generating Metabolic Pathways
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Overall ATP Production
Electron Transport System
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Citric Acid Cycle
2
Glycolysis2
SUBTOTAL
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NADH Transport into Mitochondrion*
TOTAL 36
-2
(-2) some ATP is used to pump NADH across membrane so ~ 36 ATP
The high-energy ATP molecules store 7.3 kcal of energy per mole
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Net ATP Yield
34 to 36 molecules ATP for every
glucose molecule
ATP
about 40% efficiency
The high-energy ATP molecules store 7.3 kcal of energy per mole
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What Feeds a Tumor?
NCI web site
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How is Cancer Cell Metabolism different ?
MaBhew G. Vander Heiden, Science Webinar.
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The Warburg Theory of Cancer or
"Warburg hypothesis"
Warburg hypothesis 1924
“Cancer, above all other diseases,
has countless secondary causes. But,
even for cancer, there is only one
prime cause. Summarized in a few
words, the prime cause of cancer is
the replacement of the respiration of
oxygen in normal body cells by a
fermentation of sugar… " -- Dr. Otto
H. Warburg in Lecture
On the Origin of Cancer Cells. Otto Warburg
Science 24 February 1956: 309-314.
Dr. O4o H. Warburg ( 1883 – 1970) 22
What is the Warburg Effect?
Observation that most cancer cells
predominantly produce energy through a high
rate of glycolysis followed by lactic acid
fermentation, rather than through oxidative
phosphorylation in the mitochondria.
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An Emerging Hallmark: Reprogramming Energy Metabolism
Acquired Abilities for Cancer Progression: Cancer
Hallmarks 2000 vs 2011
The uncontrolled growth and division of cancer
cells relies not only on the deregulation of cell
proliferation, but also on the reprogramming of
cellular metabolism, including increased aerobic
glycolysis (known as the Warburg effect)
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646
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Tumor Metabolism: How is it Different?
Glycolysis
MaBhew G. Vander Heiden et al, Science, 2009 25
Warburg Effect
The higher the malignancy, the greater the fermentaHon and the smaller the respiraHon
QO2: oxygen consumed/ml
QMO2: lacHc acid produced aerobically /ml
QMN2: lacHc acid produced anaerobically /ml
Science 1956;124: (3215) 269-­‐70
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Higher Glucose Uptake Correlates With More Aggressive
Phenotypes and Poorer Clinical Outcomes
Low malignancy
Nature Rev Cancer 2004;4:891-­‐9
High Malignancy
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Clinical FDG-PET Scanning Exploits
Cancer Metabolism
Cancer cells must compensate for the ~18-fold lower efficiency of ATP production
afforded by glycolysis relative to mitochondrial oxidative phosphorylation
Cancer cells upregulate glucose transporters, which substantially increases glucose
import into the cytoplasm
Cancer: Principles & Prac/ce of Oncology 9th Edi8on MaBhew G. Vander Heiden et al, Science, 2009 28
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Cancer Cell Metabolism:
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The Possible Drivers, Advantages, and Potential Liabilities of
the Altered Metabolism of Cancer Cells
Hsu PP et al. Cell. 2008 Sep 5;134(5):703-­‐7
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The Possible Advantages of the Altered Metabolism
of Cancer Cells
Altered Metabolism Provides Substrates for Biosynthe=c Pathways
Aerobic glycolysis is about 100 Hmes faster than oxidaHve-­‐
phosphorylaHon in the mitochondria
Increased glycolysis allows the diversion of glycolyHc intermediates into various biosyntheHc pathways
Facilitates the biosynthesis of the macromolecules and organelles
required for assembling new cells
Ensures that cancer cells have a ready supply of the building blocks needed for macromolecule synthesis
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Cell Proliferation Requires the Conversion
of Nutrients into Biomass
Non-proliferating Cells
NUTRIENTS
E
N
S
I R
T
U
T
ATP
Proliferating Cancer Cells
NUTRIENTS
NUTRIENTS
EN TU
S
I
T
R
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Glucose and Glutamine Feed Cell Growth and
Proliferation
Dang C V Genes Dev. 2012;26:877-890
Copyright © 2012 by Cold Spring Harbor Laboratory Press
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Most of the Increased Nutrient Uptake in Cancer is Used to Support Biosynthesis 10%
MaBhew G. Vander Heiden. Nat Rev Drug Discov. 2011 35
Pyruvate Kinase (PK-M2 ) Activity is Regulated by cell
Growth Signals and Promotes Anabolic Metabolism
CO2
Normal differentiated cells
Oxidative Phosphorylation
Proliferating cells
Aerobic Glycolysis
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PKM2 Regulates an Anabolic Program to Support Cancer Cell
Proliferation
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The Possible Drivers of the Altered
Metabolism of Cancer Cells
The tumor microenvironment selects for altered
metabolism
Hypotheses: Hypoxic conditions (A decrease in ambient O2
availability and levels)
Persistent metabolism of glucose to lactate even in aerobic conditions is
an adaptation to intermittent hypoxia in pre-malignant lesions
Upregulation of glycolysis leads to microenvironmental acidosis
requiring evolution to phenotypes resistant to acid-induced cell toxicity
Subsequent cell populations with upregulated glycolysis and acid
resistance have a powerful growth advantage, which promotes
unconstrained proliferation and invasion
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Hypoxia-Inducible Transcription Factor (HIF)
Tumors outgrows the diffusion limits of its local blood supply,
leading to hypoxia and stabilization of the hypoxia-inducible
transcription factor, HIF
HIF-1 is critical to glycolysis, induces nearly all enzyme
transcription
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HIF-1 Pathway
Meijer T W et al. Clin Cancer Res 2012;18:5585-5594
©2012 by American Association for Cancer Research
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OXPHOS
In
Mitochondria
OXPHOS-­‐ Oxida=ve Phosphoryla=on
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Linking Oncogenes and Tumor Suppressor's to Tumor Cell
Metabolism
Cancer Cell. 2008 Jun;13(6):472-­‐82
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Cancer Cell. 2008 Jun;
13(6):472-­‐82
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Signalling and Transcriptional Machinery that Regulate Metabolism:
PI3K/Akt Pathway
Cantor J R , and Sabatini D M Cancer Discovery
2012;2:881-898
©2012 by American Association for Cancer Research
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p53 and Mitochondrial Respiration
Science 2006;312:1650-­‐4
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p53 and Mitochondrial Respiration
HCT116
Science 2006;312:1650-4
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p53 and Mitochondrial Respiration
Science 2006;312:1650-4
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P53 Regulates Cellular Metabolism
Shen L et al. Clin Cancer Res 2012;18:1561-1567
©2012 by American Association for Cancer Research
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Summary: Factors Affecting Cancer Metabolism
TW Mak et al., Nat Rev Cancer, 2011
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Glycolytic Inhibitors With Anticancer Activity
Oncoene 2006; 25:4633-46 , J Bioegnerg Biomembr 2007; 39:267-74
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Glycolytic Inhibitors With Anticancer Activity
Oncogene (2006) 25, 4633–4646, J Bioenerg Biomembr. 2012 Feb;44(1):17-­‐29
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Mitochondrial Function During Oncogenesis
The possible effects of loss of supercomplex organization on mitochondrial function during
oncogenesis.
Gasparre G et al. Cold Spring Harb Perspect Biol
2013;5:a011411
©2013 by Cold Spring Harbor Laboratory Press
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Application and Integration of Tools to Study Tumor Metabolism.
Cantor J R , and Sabatini D M Cancer Discovery
2012;2:881-898
©2012 by American Association for Cancer Research
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Summary Reprogramming energy metabolism is an an emerging hallmark in deregulation of cell proliferation
The Warburg effect, or aerobic glycolysis, is the observation that most cancer cells produce energy through a high rate of
glycolysis followed by lactic acid fermentation, even in the presence of oxygen
~ 90 years after Warburg’s idea, aerobic glycolysis indeed play important roles in cancer biology
Using glucose analog FDG, PET can pinpoint the location of cancer cells
Changes in the tumor microenvironment, oncogene activation, transcription rate of enzymes and transporters involved
in glycolysis and oxidative metabolism are believed to push cancer cells into adopting aerobic glycolysis
These changes are a result of transcription factors such as HIF and p53
Drugs currently in development/clinical trials to disrupt aerobic glycolysis in cancer cells, are focused on blocking glucose
uptake, or inhibiting specific glycolytic enzymes
Cancer metabolism can cooperated into signal transduction, and serve as a route to study cancer biology
Solid tumor is heterogeneous, and each cancer cell is a function of oxygen, glucose, pH, HIF-1, and p53…, which make
targeting therapy more challenging
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References
Recommended Reading:
1. Tumor cell metabolism: cancer's Achilles' heel. Kroemer G, Pouyssegur
J.Cancer Cell. 2008 Jun;13(6):472-82.
2. Understanding the Warburg effect: the metabolic requirements of cell
proliferation. Vander Heiden MG, Cantley LC, Thompson CB. Science. 2009
May 22;324(5930):1029-33.
3. On the origin of cancer cells. WARBURG O. Science. 1956 Feb
24;123(3191):309-14.
Required Reading:
1. Cancer cell metabolism: Warburg and beyond. Hsu PP, Sabatini DM.Cell.
2008 Sep 5;134(5):703-7.
2. p53 and metabolism. Vousden KH, Ryan KM. Nat Rev Cancer. 2009 Oct;
9(10):691-700.
3. p53 regulates mitochondrial respiration. Matoba S, Kang JG, Patino WD,
Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. Science.
2006 Jun 16;312(5780):1650-3.
4. Regulation of cancer cell metabolism. Cairns RA, Harris IS, Mak TW. Nat
Rev Cancer. 2011 Feb;11(2):85-95
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